It is known that, in addition to genetic susceptibility in many diseases, environmental factors play a critical role in determining whether susceptible individuals develop the disease. However, it is not clear what these environmental factors are. The environmental factors are mostly the factors that have direct interaction with our skin and mucosal systems. Epidemiological studies have shown the sharp rise of allergy (dermatitis or food allergy), asthma, obesity and type 1 diabetes (T1D) in the US and worldwide in the past two decades. Furthermore, the rise of these human health problems is correlated with changes in our environment including our hygiene. Although genetic susceptibility, such as the MHC, play an important role in type 1 diabetes, an immune system-mediated disease, the disease process is significantly shaped by environmental factors as a) there is a significant discordance in T1D outcome in identical twins and b) the incidence of T1D is much higher in the Western world. However, little is known about how those environmental factors affect disease development. Increasing evidence suggests that commensal bacteria act as one of the important environmental factors in allergy, inflammatory bowel disease and diabetes (type 1 and type 2). In the past 20 years, diabetes has also been increasing substantially and globally. In 2008 there were about 24 million people with diabetes in the United States alone, with 5.7 million people remaining undiagnosed. Another 57 million people are estimated to have pre-diabetes (public information from the CDC). Recent studies indicated the association of commensal bacteria with diet induced obesity and type 2 diabetes. However, there is a significant gap in our knowledge and understanding of whether early exposure to certain bacteria also acts as an important environmental factor in affecting T1D development. We will address this important gap using a mouse model of human T1D. We believe that once we understand the basic mechanisms of how commensal bacteria affect T1D development, we will be able to provide better knowledge to the public and hopefully to design a preventive strategy. To improve our knowledge and understanding of the mechanism(s) of probiotic bacteria, hence the change of commensal gut flora, in T1D development, and to identify potential prevention strategy by alteration of gut flora, we propose two specific aims for this challenge topic. Aim 1. To investigate the effect of probiotic food on diabetes development. Aim 2. To investigate the role of gut dendritic cell (DC) in diabetes development. PUBLIC HEALTH RELEVANCE: It is known that, in addition to genetic susceptibility in many diseases, environmental factors play a critical role in determining whether susceptible individuals develop the disease. However, it is not clear what these environmental factors are. The environmental factors are mostly the factors that have direct interaction with our skin and mucosal systems. Epidemiological studies have shown the sharp rise of allergy (dermatitis or food allergy), asthma, obesity and type 1 diabetes (T1D) in the US and worldwide in the past two decades. Furthermore, the rise of these human health problems is correlated with changes in our environment including diet. Although genetic susceptibility, such as the MHC, play an important role in type 1 diabetes, an immune system-mediated disease, the disease process is significantly shaped by environmental factors as a) there is a significant discordance in T1D outcome in identical twins and b) the incidence of T1D is much higher in the Western world. In addition, the rise of T1D is correlated with the rise of allergy and asthma. To account for these changes in incidence and prevalence, the "Hygiene" or "Old Friends" hypothesis has been suggested. This postulates that a reduction in exposure to microorganisms in the environment can lead to a failure of immunoregulation. These "Old Friends" could either be non- saprophytic mycobacteria or lactobacilli which are not pathogenic, or helminths that cause the parasitic infections that are found in developing countries. The idea is that these organisms stimulate regulatory T cells by influencing the maturation of dendritic cells and reduce pathogenic effector cells. This may have the effect of increasing tolerance and bystander suppression, but there may also be other mechanisms which are important to investigate. Recent studies indicated the association of commensal bacteria with a variety of human diseases including allergy and diabetes. However, there is a significant gap in our knowledge and understanding of whether commensal bacteria act as important environmental factors in affecting allergy and diabetes. We will address this important gap using a mouse model of human T1D. Understanding how commensal bacteria shape our immune system, both innate and adaptive immunity, is critical to explain how inflammatory diseases including autoimmune disease, develop and to design new strategies for prevention and treatment of those diseases. Our overall hypothesis for the present study is that "friendly" commensal bacteria, as an environmental factor, can protect against diabetes development through mucosal immunity initiated by dendritic cells (DCs). We will investigate 1) the effect of neonatal environment and probiotic diet on changing gut flora and diabetes development, 2) the role of dendritic cells (DCs) in shaping gut flora and diabetes development. We believe that once we understand the basic mechanisms of how diet and commensal flora affect T1D development, we will be able to provide better knowledge to the public and hopefully to design a preventive strategy. Although we use a diabetes model system, the impact of our study is beyond T1D and could potentially apply to allergy, asthma and possibly other diseases that affect by environments.